The Bio Breeding Laboratories (BBL) rat is a new and unique laboratory model of spontaneous diabetes mellitus which offers unprecedented research potential due to the similarity of this animal's syndrome with human juvenile-onset insulin dependent diabetes. This is a request for support to investigate alterations in hepatic carbohydrate metabolism from diabetic BBL rats. The effects of diabetes upon hepatic gluconeogenesis and glycogen metabolism will be investigated in vivo using intact liver, perfused liver, isolated hepatocytes and crude liver homogenates. The production of glucose and glycogen from radiolabelled precursor substrates and the activities of "key" regulatory enzymes of glucose metabolism will be studied using these preparations. The effects of acute glucagon suppression upon hepatic gluconeogenesis and glycogen metabolism will be investigated to clarify the contribution of hyperglucagonemia to abnormal hepatic glucose metabolism and to evaluate glucagon suppression as an adjunct to insulin therapy. The dynamics of insulin binding and insulin degradation will be examined in BBL rats to broaden the existing knowledge of insulin hepatic receptor interaction in a model of classic insulin-dependent diabetes. Livers of diabetic BBL rats will be examined by electron microscopy to correlate possible morphologic abnormalities with concomitant biochemical defects. Quantitative morphometric analysis of the volume density of hepatic lysosomes will be made to clarify the role of glucagon in the genesis of hepatic autophagy. Because the liver is primarily responsible for the homeostatic regulation of blood glucose, an understanding of altered hepatic carbohydrate metabolism resulting from diabetes is imperative. These studies will systematically characterize altered carbohydrate metabolism and regulation in an exciting animal model exhibiting a diabetic syndrome analogous with human juvenile onset diabetes. The insights so gained, may ultimately be relevant to the human disease.